Human herpes simplex viruses (HSV-1 and HSV-2) cause significant morbidity and mortality in neonatal and immunocompromised populations. HSVs are cytolytic viruses which have profound impacts on their host cells. Consequences of HSV-1 infection of cultured cells include the induction of apoptosis and the concomitant synthesis of protein(s) which act to block this process. The broad, long-term objective of our research program is to determine the function of viral and cellular factors involved in apoptosis during HSV-1 infection of human cells. In this project, we are identifying the factors/events that trigger apoptosis during infection and the genes encoding the proteins responsible for its prevention. We showed that HSV-1 induction of apoptosis in human cells occurs in the absence of de novo viral protein synthesis. Our preliminary data indicates that viral entry is not sufficient to induce the process. In our first aim, the hypothesis which we are testing is that the initiation of viral gene expression is the trigger of apoptosis in infected human cells. We also showed that an anti-apoptotic activity is synthesized between 3 and 6 hours after HSV-1 infection of human cells. In our second aim, the hypothesis we are testing is that virally-induced factor(s) are responsible for the anti-apoptotic function. The goal of these studies is to isolate genes involved in blocking of apoptosis during infection using a combination of biochemical and molecular genetic techniques. These studies are designed to help elucidate the complexities of apoptotic programmed cell death during the replication of this important human pathogen.